WO2024003377A1 - Composition nutritionnelle pour traiter un accident vasculaire cérébral - Google Patents

Composition nutritionnelle pour traiter un accident vasculaire cérébral Download PDF

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Publication number
WO2024003377A1
WO2024003377A1 PCT/EP2023/068080 EP2023068080W WO2024003377A1 WO 2024003377 A1 WO2024003377 A1 WO 2024003377A1 EP 2023068080 W EP2023068080 W EP 2023068080W WO 2024003377 A1 WO2024003377 A1 WO 2024003377A1
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vitamin
composition
choline
per
stroke
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PCT/EP2023/068080
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English (en)
Inventor
Ladislaus Maria Broersen
Paul Johannes Maria SAVELKOUL
Nick VAN WIJK
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N.V. Nutricia
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Publication of WO2024003377A1 publication Critical patent/WO2024003377A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/14—Quaternary ammonium compounds, e.g. edrophonium, choline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4415—Pyridoxine, i.e. Vitamin B6
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A61K31/51—Thiamines, e.g. vitamin B1
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/525—Isoalloxazines, e.g. riboflavins, vitamin B2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A61K31/593—9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7135—Compounds containing heavy metals
    • A61K31/714—Cobalamins, e.g. cyanocobalamin, i.e. vitamin B12
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K33/04—Sulfur, selenium or tellurium; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
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    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention is in the field of compositions and nutritional composition for use in treating stroke, preferably the consequences of ischemic stroke.
  • the invention further pertains to reducing the risk of recurrent stroke.
  • a stroke also known as a cerebral vascular accident (CVA) is the rapid loss of brain function(s) due to disturbance in the blood supply to the brain.
  • the World Health Organization (WHO) has defined stroke as, “rapidly developing clinical signs of focal (or global) disturbance of cerebral function, with symptoms lasting 24 hours or longer or leading to death, with no apparent cause other than of vascular origin”.
  • a stroke can be due to ischemia (lack of blood flow) caused by blockage of adequate blood flow to a section of the brain, usually caused by thrombus or other emboli lodging or forming in one of the blood vessels supplying the brain occurs resulting in ischemic stroke, or when a blood vessel bursts (or ruptures) as occurs in a haemorrhagic stroke.
  • Brain ischemia also known as cerebral ischemia, is a resulting condition in which there is insufficient blood flow to the brain to meet metabolic demand.
  • the ischemia may be focal ischemia, which is confined to a specific region of the brain, yet also global ischemia, which encompasses wide areas of brain tissue. If a blockage in ischemic stroke is not quickly resolved, the ischemia may cause the brain to become hypoxic leading to permanent neurologic damage or death.
  • the consequences of strokes can be devastating and include impaired motor skills, impaired vision, and linguistic impairment.
  • the most common cause of ischemic stroke is occlusion of the middle cerebral artery (the intra-cranial artery downstream from the internal carotid artery), which damages cerebrum (e.g., cerebral cortex), e.g., the motor and sensory cortices of the brain.
  • cerebrum e.g., cerebral cortex
  • Such damage may result in hemiplegia, hemi-anaesthesia and, depending on the cerebral hemisphere damaged, either language or visuo-spatial deficits.
  • stroke is a main cause of death and disability worldwide, with one among every seven individuals suffering from stroke in their lifetime, and ischemic stroke accounting for more than 80% of strokes (Lackland et al., 2014).
  • Effective treatments after stroke include reperfusion therapies, such as with recombinant tissue plasminogen activator; but this must be administered in a limited time window (within 4.5 hours of stroke onset); therefore, only 2-4% patients benefit from it (Hankey, 2017).
  • Disability after stroke brings serious social and economic burdens; few people spontaneously recover and many are permanently disabled (Koh and Park, 2017).
  • WO2019/074617 relates to multi-nutrient compositions enhancing the neurological function of a human through a.o. promoting neurite outgrowth.
  • the multi-ingredient composition comprises high levels of vitamin K2 together with amongst others co-enzyme Q10, vitamin D3, cholecalciferol or ergocalciferol, and phosphatidyl choline.
  • Fernandez-Vega et al. Nutrients, 2020 relates to nutritional supplementation with different separate supplements including supplements with coenzyme Q10 (100 mg per day) and vitamin B2 (0.7 mg of vitamin B2 and 25 mg of coenzyme Q10 per day) for the treatment of vascular occlusion diseases affecting the retina, yet does not disclose a nutritional composition comprising a combination of coenzyme Q10 with both vitamin D and vitamin B2 for the treatment of the consequences of a stroke.
  • WO02/28379 A2 describes compositions and methods for lowering plasma lipoprotein(a) (Lp(a)) in humans and reducing the risk factors of a broad range of cardiovascular diseases, yet lacks an unambiguous disclosure of any combination of nutrient for use in the treatment of stroke.
  • WO2019/165222 A1 describes a nutritional supplement of coQ10, vitamin B and vitamin D designed to support kidney and cardiac functions as well as mitochondrial energy function needs in patients undergoing haemodialysis yet does not disclose the treatment of (the consequences of) stroke.
  • US2014/314731 A1 describes a composition consisting of Vitamin C, L-glutamine, L-cystine or L- cysteine, riboflavin, succinic acid, fumaric acid, coenzyme Q10, and niacin, and the use of this composition for minimizing the cell-damaging effect of radicals and harmful forms of oxygen, in particular of oxygen radicals or reactive oxygen species.
  • Chelluboina Barrath et al. Neurochemistry international, 2020 discloses the therapeutic potential of nutraceuticals to protect brain after stroke yet does not disclose the use of any specific combination nutraceuticals.
  • EP2938350 A1 discloses that an underlying cause of stroke is hypercholesterolemia which can be prevented by providing formulations that are able to lower LDL cholesterol blood levels, improve total cholesterol blood levels, increase HDL blood levels, lower triglyceride blood levels, and/or lower the systolic blood pressure.
  • Said formulation comprises co-enzyme Q10, fish oil comprising eicosapentaenoic acid and docosahexaenoic acid, as well as vitamin D3.
  • a composition comprising a combination of therapeutically effective amounts of co-enzyme Q10, vitamin D and vitamin B2 is effective in the treatment of stroke, in particular ischemic stroke.
  • Treatment of stroke includes treatment of the consequences of a stroke. It was found in an in vitro model that a composition comprising a combination of co-enzyme Q10 and vitamin D, a combination of co-enzyme Q10 and vitamin B2, as well as a combination of co-enzyme Q10, vitamin D and vitamin B2 results in an increase of the outgrowth of neurites from surviving neurones after hypoxia and a reduction in neuronal damage after hypoxia as compared to without a composition comprising a combination of co-enzyme Q10 and vitamin D and/or vitamin B2.
  • a combination of co-enzyme Q10 and vitamin D together with vitamin B2, B6 or B9 shows a beneficial improvement in neurite outgrowth after hypoxia
  • (i) Co-enzyme Q10 in combination with (ii) vitamin D and (iii) vitamin B2, together with (iv) polyunsaturated fatty acids and (v) choline, preferably phosphatidylcholine also beneficially increased outgrowth of neurites from surviving neurones after hypoxia and a reduction in neuronal damage.
  • the present invention thus concerns a method for treating stroke in a subject, preferably wherein the stroke is ischemic stroke, comprising administering to the subject a composition according to the invention.
  • the invention further pertains to a composition comprising a combination of (i) co-enzyme Q10 (ii) vitamin D and (iii) vitamin B2.
  • the composition comprises a combination of co-enzyme Q10, vitamin D and vitamin B2 in combination with one or more of vitamin B6, and B9.
  • the composition optionally further comprises (iv) polyunsaturated fatty acids and (v) choline.
  • the invention thus also pertains to a composition
  • a composition comprising a combination of (i) co-enzyme Q10 (ii) vitamin D, (iii) vitamin B2, (iv) polyunsaturated fatty acids and (v) choline.
  • the composition according to the invention further comprises one of more selected from A, B, C and E vitamin(s), phospholipids, selenium, and magnesium.
  • the composition according to the invention comprises a combination of co-enzyme Q10, vitamin D, vitamin B2, polyunsaturated fatty acids, choline and one or more further B vitamins.
  • the invention concerns a method for treating stroke in a subject, preferably wherein the stroke is ischemic stroke, comprising administering to the subject the composition according to the invention.
  • the invention may also be worded as the use of a therapeutically effective combination of (i) co-enzyme Q10 with (ii) vitamin D and (iii) vitamin B2, for the manufacture of a composition for treating stroke in a subject, preferably ischemic stroke.
  • the invention may in a further embodiment be worded as the use of a therapeutically effective combination of co-enzyme Q10, vitamin D and vitamin B2 in combination with one or more of vitamin B6, and B9 for the manufacture of a composition for treating stroke in a subject, preferably ischemic stroke.
  • the invention relates to the use of a therapeutically effective combination of (i) co-enzyme Q10 with (ii) vitamin D and (iii) vitamin B2, and optionally (iv) polyunsaturated fatty acids and (v) choline for the manufacture of a composition for treating stroke in a subject, preferably ischemic stroke.
  • the invention concerns a composition for use in the treatment of stroke in a subject, preferably wherein the stroke is ischemic stroke, said composition comprising a combination of (i) co-enzyme Q10 with (ii) vitamin D and (iii) vitamin B2, and optionally further comprising (iv) polyunsaturated fatty acids and/or (v) choline.
  • the invention particularly pertains to treating or preventing the consequences of stroke, preferably ischemic stroke, which involves an improvement (e.g., increase) in neurite length in treated subjects as compared with subjects not treated with the composition according to the invention.
  • treatment of stroke, preferably ischemic stroke further involves neuroprotection after stroke.
  • the invention particularly pertains to treating or preventing the consequences of stroke, preferably ischemic stroke, which involves a prevention of or improvement in functional consequences of a stroke such as but not limited to hemiplegia, hemi-anaesthesia, language, or visuo-spatial deficits.
  • the invention further pertains to preventing or reducing the risk of a second or recurrent stroke in a patient, since patients having suffered from a first stroke (‘first-ever stroke’) are at increased risk of having another stroke within their lifetime.
  • first stroke a first stroke
  • Recurrent strokes often have a higher rate of death and disability because parts of the brain already injured by the original stroke may not be as resilient.
  • the administration or use of the composition is initiated after a stroke has occurred or has been diagnosed and the administration or use of the composition continues for a period of at least 2 weeks.
  • a daily supplementation of 5 to 90 mg of Co-enzyme Q10 with 5-80 ug of vitamin D, preferably vitamin D3 and 0.8 to 7.6 mg vitamin B2 is provided with the composition according to the invention.
  • FIG. 1 The effects of co-enzyme Q10, vitamin D3, vitamin B2 and their combination on neurite outgrowth in primary neurons after hypoxia are shown. Neurite outgrowth is expressed as percentage relative to control (100%).
  • a nutritional composition comprising a combination of (i) co-enzyme Q10, (ii) vitamin D and (iii) vitamin B2, for use in the treatment of stroke, preferably ischemic stroke.
  • composition for use according to embodiment 1 wherein the composition further comprises (iv) polyunsaturated fatty acids and (v) choline, preferably (iv) polyunsaturated fatty acids selected from DHA, EPA and/or DPA and (v) choline.
  • choline is provided in the form of free choline, a choline salt and/or choline ester, wherein the choline ester is preferably phosphatidyl choline.
  • composition for use according to any one of embodiments 1 to 3 wherein the composition further comprises one or more of (vi) vitamin B6 and (vii) vitamin B9.
  • the nutritional composition for use according to the any one of preceding embodiments wherein the treatment of stroke comprises an increase in length of neuronal neurite outgrowth in subjects suffering from stroke and treated with the composition as compared with subjects suffering from stroke and not treated with the composition.
  • composition for use according to any one of the preceding embodiments wherein the composition is used for at least 2 weeks, preferably at least 4 weeks after diagnosis of the stroke.
  • composition comprises daily dosages of:
  • the nutritional composition for use according to any one of the preceding embodiments further comprising one of more selected from A, C, and E vitamin(s), phospholipids, selenium, magnesium, and further B vitamins.
  • composition for use according to any one of the preceding embodiments wherein the composition comprises v a ) phosphatidylcholine and Vb) choline or a salt thereof, and wherein the weight-to-weight ratio phosphatidylcholine to choline is more than 0.1 .
  • Liquid nutritional composition comprising a combination of
  • vitamin D preferably vitamin D3
  • polyunsaturated fatty acids selected from DHA, EPA and/or DPA, more preferably DHA and/or EPA; and, (v) choline, choline salts and/or choline esters; and optionally at least one of (vi) vitamin B6 and (vii) vitamin B9.
  • Liquid nutritional composition according to embodiment 14 wherein the composition comprises per 100 kcal
  • Liquid nutritional composition according to any one of embodiments 14 and 15 wherein the composition further comprises one of more selected from A, further B, C, E and K vitamin(s), phospholipids, selenium and magnesium.
  • Liquid nutritional composition according to any one of embodiments 14 to 16 wherein the composition further comprises per 100 kcal one or more of
  • Liquid nutritional composition according to any one of embodiments 14 to 17 wherein the composition further comprises per 100 kcal one or more of
  • Liquid nutritional composition according to any one of embodiments 14 to 18 wherein the composition comprises phosphatidylcholine and choline, and wherein the weight-to-weight ratio phosphatidylcholine to choline is more than 0.1 .
  • Liquid nutritional composition according to any one of embodiments 14 to 19, wherein the composition has a caloric density between 1 .0 and 2.5 kcal per ml, preferably 1 .2 and 2.4 kcal per ml.
  • Liquid nutritional composition according to embodiments 14 to 20 wherein the composition 4 to 7g protein per 100 kcal, 3 to 5.5 g lipids per 100 kcal and 8.5 to 10.5g carbohydrates per 100 kcal.
  • the present invention concerns a method for treating stroke in a subject, preferably wherein the stroke is ischemic stroke, wherein the method involves administration of a composition to a subject, said composition comprising a combination of (i) co-enzyme Q10 with (ii) vitamin D and (iii) vitamin B2, optionally further comprising (iv) polyunsaturated fatty acids and/or (v) choline, preferably (iv) polyunsaturated fatty acids and (v) choline.
  • the composition comprises a combination of co-enzyme Q10 and vitamin D in combination with vitamin B2 and one or more of B6, and B9.
  • the composition according to the invention further comprises one of more selected from A, B, C and E vitamin(s), phospholipids, selenium, and magnesium.
  • the invention also concerns the use of a composition comprising a combination of (i) coenzyme Q10 with (ii) vitamin D and (iii) vitamin B2 and optionally (iv) polyunsaturated fatty acids and/or (v) choline for the manufacture of a composition for treating stroke in a subject, preferably ischemic stroke.
  • the composition according to the invention further comprises one of more selected from A, B, C and E vitamin(s), phospholipids, selenium, and magnesium.
  • the invention pertains to a composition for use in the treatment of stroke in a subject, wherein the stroke is preferably ischemic stroke, said composition comprising a combination of (i) co-enzyme Q10 with (ii) vitamin D and (iii) vitamin B2, and optionally (iv) polyunsaturated fatty acids and/or (v) choline.
  • the composition according to the invention further comprises one of more selected from A, B, C and E vitamin(s), phospholipids, selenium, and magnesium.
  • the composition comprises a combination of co-enzyme Q10 and vitamin D in combination with vitamin B2 and one or more of B6, and B9.
  • the invention further particularly pertains to treating stroke, more in particular treating or preventing the consequences of stroke, preferably ischemic stroke.
  • the treatment of stroke, preferably ischemic stroke involves an improvement (e.g., increase) in neurite length in subjects treated with the composition according to the invention as compared with subjects not treated with the composition according to the invention.
  • treatment of stroke, preferably ischemic stroke further involves neuroprotection after stroke.
  • the treatment of stroke, preferably ischemic stroke further includes an improvement of post-hypoxic recovery of neurons and a reduction in inflammatory and oxidative processes.
  • the treatment of stroke thus involves neuronal repair or regeneration and recovery of neuronal networks after a stroke has occurred.
  • the treatment of stroke includes neuroprotection of neurons exposed to hypoxia.
  • treatment of stroke preferably ischemic stroke
  • the invention particularly pertains to treating or preventing the consequences of stroke, preferably ischemic stroke, which involves a prevention of or improvement in functional consequences of a stroke such as but not limited to hemiplegia, hemi-anaesthesia, language, or visuo-spatial deficits.
  • co-enzyme Q10 beneficially mitigates oxidative damage thereby aiding in reducing the extent of neuronal damage following hypoxia.
  • vitamin B6 and B9 further enhances the antioxidant capacity of co-enzyme Q10 together with vitamin D3 and allows to mitigate oxidative damage and promote neuronal recovery.
  • Polyunsaturated fatty acids in turn beneficially support brain metabolism, cell survival and provide anti-inflammatory action thereby supporting healing or recovery post hypoxia.
  • Choline is associated with decreased neuroinflammation, improved functional and structural connectivity, had beneficial effects on cerebral blood flow.
  • the ingredients of the composition according to the invention are believed to provide on one hand an optimal promotion of neurite outgrowth and recovery after hypoxia while at the same time supporting brain function.
  • Nutritional composition means a substance or formulation that satisfies at least a portion of a subject's nutrient requirements.
  • the terms “nutritional(s)”, “nutritional formula(s)”, “enteral nutritional(s)”, and “nutritional supplement(s)” are used as non-limiting examples of nutritional composition(s) throughout the present disclosure.
  • nutritional composition(s) may refer to liquids, powders, gels, pastes, solids, concentrates, suspensions, or ready-to-use forms of enteral formulas, oral formulas, formulas for infants, formulas for pediatric subjects, formulas for children, growing-up milks and/or formulas for adults.
  • supplement refers to a nutritional product that provides nutrients to an individual that may otherwise not conveniently be consumed in sufficient quantities by said individual and may be used to complement the nutrition of an individual. It may be in the form of tablets, capsules, pastilles or a liquid and the like. Supplements typically provide the selected nutrients while not representing a significant portion of the overall nutritional needs of the subject. Typically, they do not represent more than 0.1 %, 1 %, 5%, 10% of the daily energy need of the subject.
  • neuronal repair refers to promotion of neuronal repair, limiting neuronal oxidative stress, limiting cell damage and/or promotion of recovery of neuronal networks after stroke.
  • Prevention includes reduction of risk and/or severity of neuronal damage from strokes.
  • treatment includes both prophylactic or preventive treatment (that prevent and/or slow the development of a targeted pathologic condition or disorder) and curative, therapeutic or disease-modifying treatment, including therapeutic measures that cure, slow down, lessen symptoms of, and/or halt progression of a diagnosed pathologic condition or disorder; and treatment of patients at risk of contracting a disease or suspected to have contracted a disease, as well as patients who are ill or have been diagnosed as suffering from a disease or medical condition.
  • the term does not necessarily imply that a subject is treated until total recovery.
  • treatment also refer to the maintenance and/or promotion of health in an individual not suffering from a disease but who may be susceptible to the development of an unhealthy condition.
  • treatment also intended to include the potentiation or otherwise enhancement of one or more primary prophylactic or therapeutic measure.
  • treatment also intended to include the dietary management of a disease or condition or the dietary management for prophylaxis or prevention a disease or condition in a subject in need thereof.
  • the subject as used herein is a mammal, preferably a human.
  • a “therapeutically effective amount” is an amount that reduces symptoms, manages progression of the consequences of stroke or provides a nutritional, physiological, or medical benefit to the individual.
  • neurite refers to processes growing out of a neuron.
  • neurite as used herein encompasses all such cell processes (including both axons and dendrites) growing out of a neuron.
  • neuron outgrowth refers to the process of cells growing out of a neuron, or to the cells comprising an outgrowth from a neuron.
  • the method or use or composition for use according to the invention involves administration of the composition according to the invention.
  • the composition according to the invention may be used as a pharmaceutical product or a nutritional product.
  • the present nutritional composition is a liquid.
  • the present nutritional composition is a liquid ready-to-feed composition.
  • the composition is administered orally or as tube feed.
  • the composition according to the invention may be used as a pharmaceutical product comprising one or more pharmaceutically acceptable carrier materials.
  • Such product may contain the daily dosages as defined below in one or more dosage units.
  • the dosage unit may be in a liquid form or in a solid form, wherein in the latter case the daily dosage may be provided by one or more solid dosage units, e.g. in one or more capsules or tablets.
  • the pharmaceutical product preferably for enteral application, may be a solid or liquid galenical formulation. Examples of solid galenical formulations are tablets, capsules (e.g. hard or soft shell gelatine capsules), pills, sachets, powders, granules and the like which contain the active ingredients together with conventional galenical carriers. Any conventional carrier material can be utilized.
  • the carrier material can be organic or inorganic inert carrier material suitable for oral administration.
  • Suitable carriers include water, gelatine, gum Arabic, lactose, starch, magnesium stearate, talc, vegetable oils, and the like. Additionally, additives such as thickeners, flavouring agents, preservatives, stabilizers, emulsifying agents, buffers and the like may be added in accordance with accepted practices of pharmaceutical compounding. While the individual active ingredients are suitably administered in a single composition, they may also be administered in individual dosage units.
  • the composition according to the invention may be used as a nutritional product, for example as a nutritional supplement, e.g. as an additive to a normal diet, as a fortifier, to add to a normal diet, or as a complete nutrition.
  • the nutritional product preferably comprises at least one component, preferably all components, selected from the group of fats, proteins, and carbohydrates. It is understood that a nutritional product differs from a pharmaceutical product by the presence of nutrients which provide nutrition to the subject to which the composition is administered, in particularthe presence of protein, fat, digestible carbohydrates and dietary fibres. It may further contain ingredients such as minerals, vitamins, organic acids, and flavouring agents.
  • the term "nutraceutical product” is often used in literature, it denotes a nutritional product with a pharmaceutical component or pharmaceutical purpose. Hence, the nutritional composition according to the invention may also be used in a nutraceutical product.
  • the composition comprises a lipid fraction , wherein the lipid fraction provides between 15 and 50 energy% of the composition.
  • the composition is a liquid composition containing between 1.1 and 2.6 kcal per ml, preferably between 1 .2 and 2.4 kcal per ml.
  • the composition is a tube feed having a caloric density of between 1.1 and 1 .7 kcal per ml, preferably between 1.2 and 1.6 kcal per ml.
  • the composition is in the form of an oral nutritional supplement having a caloric density of between 2.2 and 2.6 kcal per ml.
  • the energy provided by nutrients is calculated using the Atwater calculation factors of 9 kcal per g lipid, 4 kcal per gram protein or gram digestible carbohydrate, 2 kcal per gram fiber and zero kcal for the other components in the product.
  • the amount of lipid fraction can be determined by applying the methods known in the art for measuring fat content in the food matrix as applicable. For example, fat content for general foods is determined by applying AOAC(R) official method 983.23, while the Roese-Gott Kunststoff method (AOAC(R) 932.06) is better applicable for products based on dried milk (Lehner, R., Estoppey, A., (1954) Mitt. Strukturuntersuchung Hyg. 54:183-185).
  • the amount of individual lipid components can be determined by applying methods specifically designed for measuring that specific component or by fractionating the fat fraction isolated from the extraction of the chloroform-niethanol fraction as given in the 983.23 method.
  • Suitable sources of lipids for use in the composition include but are not limited to fish oil, krill oil, algae oil, soybean oil, rape seed oil (such as colza oil, low erucic acid rape seed oil and canola oil), high oleic sunflower oil, coconut oil, high oleic safflower oil and olive oil.
  • lipids obtained from milk from non-human mammals preferably cow's milk, goat milk, sheep milk, horse milk, buffalo milk, yak milk, reindeer milk, donkey milk and camel milk, particularly cow's milk and/or goat milk. Milk lipid is sometimes also referred to as milk fat or butter fat.
  • the nutritional composition according to the invention thus preferably comprises a lipid fraction, preferably a lipid fraction suitable for nutrition as known in the art.
  • the composition comprises 4 to 12 g lipid per 100 ml, preferably 4.5 to 11 g lipid per 100 ml, more preferably 5 to 10 g per 100 ml.
  • the compostion according to the invention may comprise 3 to 5.5 g of lipid per 100 kcal, preferably 3.5 to 5 g per 100 kcal, more preferably 3.8 to 4.5 g of lipid per 100 kcal based on the total energy content of the composition.
  • the lipid fraction includes polyunsaturated fatty acids and optionally also mono-unsaturated fatty acids (MUFAs) and saturated fatty acids (SFA).
  • MUFAs mono-unsaturated fatty acids
  • SFA saturated fatty acids
  • the composition according to the invention preferably comprises 4 to 17 g of protein per 100 ml of the composition.
  • the total protein that is present in the nutritional composition i.e. the combination of all proteins present, may also be referred to as the “protein fraction” of the nutritional composition.
  • the nutritional composition thus preferably comprises a protein fraction of 4 - 17 g per 100 ml of the composition.
  • the nutritional composition comprises a protein fraction of 5 to 16 g per 100 ml of the composition, more preferably of 6 - 15 g.
  • Most preferably the composition comprises a protein fraction of 11 to 14.5 g per 100 ml of the composition.
  • the compostion according to the invention may comprise 4 to 7 g of protein fraction per 100 kcal, preferably 4.5 to 6.5 g of protein fraction per 100 kcal, more preferably 5 to 6 g of protein fraction per 100 kcal based on the total energy content of the composition.
  • Suitable protein sources may be based on cows' milk proteins such as whey, casein and mixtures thereof and vegetable proteins such as those based on soy, potato, pea and the like.
  • the nutritional composition preferably further comprises a carbohydrate fraction.
  • the composition preferably comprises 9 to 25 g carbohydrates per 100 ml, more preferably 10 to 24 g per 100 ml, even more preferably 11 to 23 per 100 ml.
  • the compostion according to the invention may comprise 8.5 to 10.5 g of carbohydrates per 100 kcal, preferably 9 to 10 g per 100 kcal, more preferably 9.2 to 9.6 g of carbohydrates per 100 kcal based on the total energy content of the composition.
  • Suitable carbohydrate sources include lactose, glucose, sucrose, fructose, galactose, maltose, starch, isomaltulose, and maltodextrin.
  • the composition of the invention is typically an enteral composition, i.e. intended for oral administration such as a tube feed, a nutritional drink and an oral nutritional supplement. It is preferably administered in liquid form.
  • the composition comprises water in which the further components are dissolved or suspended.
  • the composition is thus preferably a liquid, or a solid (typically a powder or tablet, preferably a powder) which is reconstitutable with a liquid, preferably with water, to obtain a liquid composition.
  • a liquid preferably with water
  • Dosages of components defined below may for example be in daily dose or in a concentration per 100 mL or 100 kcal.
  • the composition according to the invention is for treating stroke, preferably ischemic stroke.
  • the stroke is preferably an ischemic stroke, which may also be referred to as ischemic event, ischemic episode, ischemic attack or cerebral infarction and the treatment particularly involves treatment of the consequences of a stroke.
  • the treatment involves an improvement in neurite outgrowth.
  • compositions as described above can be used as a nutritional therapy, nutritional support, as a medical food, as a food for special medical purposes or as a nutritional supplement.
  • Administration of the composition according to the invention typically occurs during recovery and/or rehabilitation afterthe occurrence of a stroke, and may be continued as long as negative effects thereof prolong. Although positive effects are already observed during the first week of administration, administration is preferably continued for at least 2 weeks, more preferably at least 4 weeks, even more preferably at least 8 weeks. Administration preferably starts at the first day after occurrence of a stroke.
  • the composition according to the invention can be consumed in the form of a liquid composition, preferably an oral nutritional supplement at one, two or three servings of 50 - 250 mL per day, typically servings of 125 mL each, during recovery and/or rehabilitation after the occurrence of a stroke.
  • Preferred daily dosages are in the range of 100 to 500 mL, more preferably 125 to 375 mL, most preferably 200 to 300 mL.
  • the composition is enterally administered. Administration occurs preferably at least one time per day, although alternative dosage regimes can be determined from these numbers.
  • the composition may be a tube feed and is administered continuously.
  • Preferred daily dosages of a tube feed are in the range of 1000 to 3000 kcal per day, preferably 1500 kcal to 2500 kcal per day. Preferably about 1 to 2 liters of tube feed is administered per day.
  • composition comprising a combination of (i) co-enzyme Q10 with (ii) vitamin D and (iii) vitamin B2, optionally further comprising (iv) polyunsaturated fatty acids and/or (v) choline.
  • the composition comprises a combination of co-enzyme Q10 and vitamin D, in combination with vitamin B2, and optionally one or more of B6, and B9.
  • Said composition optionally further comprises (iv) polyunsaturated fatty acids and/or (v) choline.
  • the composition according to the invention further comprises one of more selected from A, further B, C, and E vitamin(s), phospholipids, selenium and magnesium.
  • composition according to the invention comprises therapeutically effective amounts of Co-enzyme Q10.
  • composition according to the invention comprises co-enzyme Q10 in combination with vitamin D and vitamin B2.
  • composition according to the invention may comprise a combination of co-enzyme Q10, vitamin D and vitamin B2, in combination with one or more of vitamin B6, and B9.
  • composition according to the invention may comprise a combination of co-enzyme Q10, vitamin D and vitamin B2, in combination with polyunsaturated fatty acids and/or choline.
  • Co-enzyme Q10 (also known as CoQ10, Q10, vitamin Q10, ubiquinone, and ubidecarenone) is a benzoquinone compound synthesized naturally by the human body.
  • the "Q” and the “10” in the name refer to the quinone chemical group and the 10 isoprenyl chemical subunits, respectively, that are part of this compound's structure.
  • Co-enzyme Q10 as used herein refers to ubiquinone (2,3 dimethoxy-5 methyl-6-decaprenyl benzoquinone) and/or its functional analogues including ubiquinol.
  • Co-enzyme Q10 is a natural substance soluble in fats that plays a main role as an enzyme cofactor necessary in the transporting chain of mitochondrial electrons, and it is key factor in oxidative phosphorylation and aerobe cell breathing by generating adenosine triphosphate (ATP) (Egil Fosslien; Mitochondrial Medicine - Molecular Pathology of Defective Oxidative Phosphorylation, Annals of Clinical and Laboratory Science, 2000).
  • ATP adenosine triphosphate
  • CoQ10 was proven to act both as an antioxidant and as an electron carrier due to its lipid solubility and its capacity to exist in both completely reduced forms (ubiquinol) and completely oxidized forms (ubiquinone).
  • CoQ10 accepts electrons derived from both complex I (NADH ubiquinone oxido reductase) and complex II (succinate ubiquinone reductase), and then transports them to complex III (ubiquinol cytochrome c reductase).
  • Natural sources of CoQ10 and/or analogues that are suitable for this invention include extracts or isolates of fungi, yeasts or bacteria, canola oil or soybean oil.
  • the present composition preferably comprises 1 to 15 mg Co-enzyme Q10 per 100 ml, preferably 1.5 to 14 mg Co-enzyme Q10 per 100 ml, more preferably 2 to 13 mg Co-enzyme Q10 per 100 ml, even more preferably 2.5 to 12 mg Co-enzyme Q10 per 100 ml composition.
  • Co-enzyme Q10 is preferably provided in an amount of 5 to 90 mg per day, more preferably 8 to 80 mg per day, even more preferably 10 to 70 mg per day, most preferably 15 to 60 mg per day.
  • the composition is in the form of a tube feed and Co-enzyme Q10 is preferably provided in an amount of 8 to 75 mg per day, more preferably 10 to 70 mg per day, even more preferably 15 to 65 mg per day, most preferably 20 to 60 mg per day.
  • Co-enzyme Q10 is preferably provided in an amount of 8 to 60 mg per day, more preferably 10 to 55 mg per day, even more preferably 12 to 50 mg per day, most preferably 15 to 45 mg per day.
  • the nutrional compostion according to the invention comprises 1 .5 to 5.5 mg Co-enzyme Q10 per 100 kcal, preferably 1.8 to 5.2 mg Co-enzyme Q10 per 100 kcal, more preferably 2 to 5 mg Co-enzyme Q10 per 100 kcal based on the total energy content of the nutritional composition.
  • the above numbers are based on the molar weight of ubiquinone.
  • the present composition may comprise vitamin D.
  • the composition comprises coenzyme Q10 and vitamin D.
  • the composition according to the invention may comprise a combination of co-enzyme Q10 and vitamin D, in combination with vitamin B2 and optionally one or more of vitamin B6, and B9.
  • the composition according to the invention may comprise a combination of co-enzyme Q10, vitamin D and vitamin B2, in combination with polyunsaturated fatty acids and/or choline, preferably in combination with polyunsaturated fatty acids and choline.
  • Vitamin D is a group of fat-soluble secosteroids, the two major physiologically relevant forms of which are vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol). These are known collectively as calciferol. Vitamin D without a subscript refers to all forms of vitamin D, either D1 , D2, D3, or D4, in particular D2 and D3, or any mixture thereof.
  • the composition according to the invetion preferably comprises vitamin D3.
  • vitamin D When ingested, vitamin D is hydroxylated in the liver (endoplasmic reticulum) to 25- hydroxycholecalciferol (25(OH)D), also known as calcidiol, by the enzyme 25-hydroxylase, produced by hepatocytes. Once made, the product is stored in the hepatocytes until it is needed and can be released into the plasma where it will be bound to an a-globulin. 25-hydroxycholecalciferol is then transported to the proximal tubules of the kidneys where it can be hydroxylated by one of two enzymes to different forms of vitamin D, one of which is active vitamin D (1 ,25(OH)2D) and another which is inactive vitamin D (24,25(OH)D).
  • 25(OH)D also known as calcidiol
  • the enzyme 1a-hydroxylase which is activated by parathyroid hormone (and additionally by low calcium or phosphate) forms the main biologically active vitamin D hormone with a C1 hydroxylation forming 1 ,25- dihydroxycholecalciferol (1 ,25(OH)2D, also known as calcitriol).
  • a separate enzyme hydroxylates the C24 atom forming 24R,25(OH)2D3 when 1a-hydroxylase is not active, this inactivates the molecule from any biological activity.
  • Vitamin D may be provided in an active (1 ,25(OH)2D) or unactive (Vit D3 or D2) form.
  • the present composition preferably comprises 1 .5 to 10 pg vitamin D, preferably 2 to 9 pg vitamin D per 100 ml, more preferably 2.5 to 8 pg vitamin D per 100 ml composition.
  • vitamin D preferably vitamin D3 is supplemented in an amount of 5 to 80 pg per day, preferably 6 to 75 pg per day, more preferably 8 to 70 pg per day, even more preferably 10 to 65 pg per day.
  • the composition is in the form of a tube feed and vitamin D, preferably vitamin D3, is preferably provided in an amount of 14 to 80 pg per day, more preferably 16 to 75 pg per day, even more preferably 18 to 70 pg per day, most preferably 20 to 65 pg per day.
  • vitamin D3 is preferably provided in an amount of 5 to 45 pg per day, more preferably 6 to 40 pg per day, even more preferably 8 to 35 pg per day, most preferably 10 to 30 pg per day.
  • the nutrional compostion according to the invention comprises 1 .3 to 4.5 pg vitamin D, preferably vitamin D3, per 100 kcal, preferably 1.5 to 4 pg vitamin D per 100 kcal, more preferably 2 to 3.5 pg per 100 kcal based on the total energy content of the nutritional composition.
  • the above numbers are based on the molar weight of vitamin D3.
  • the present composition may further comprise a B-vitamin.
  • B-vitamins are known as nutritional cofactors that act as biochemical “spark plugs” in mitochondria, and therefore act to further nurture and support optimal neural metabolism.
  • the composition compises co-enzyme Q10 and at least vitamin D and vitamin B2.
  • the composition comprises co-enzyme Q10 vitamin D and vitamin B2, optionally together with vitamin B6 and/or vitamin B9..
  • the present composition preferably comprises at least one vitamin B and preferably at least two B vitamins selected from the group of vitamin B1 (thiamine), B2 (riboflavin), B3 (niacin or niacinamide), vitamin B5 (pantothenic acid), B6 (pyridoxine, pyridoxal, or pyridoxamine, or pyridoxine hydrochloride), vitamin B7 (biotin) vitamin B9 (folic acid or folate), and vitamin B12 (cobalamins). Functional equivalents are encompassed within these terms.
  • vitamin B12 incorporates all cobalamin equivalents known in the art.
  • B vitamins in the context of the composition according to the invention comprises at least one, preferably at least two even more preferably at least three selected from the group of vitamin B1 , B2, B3, B5, B6, B7, vitamin B12 and vitamin B9. More preferably the composition comprises at least one of vitamin B2, B6 and/or B9. In a further preferred embodiment the composition comprisesone or more of vitamin B2, B6 and/or B9, preferably vitamin B2, B6 and B9, more preferably vitamin B2, B6, B9 and B12, even more preferably vitamin B1 , vitamin B2, vitamin B6, vitamin B9 and vitamin B12 .
  • the composition according to the invention may include all of vitamin B1 (thiamine), B2 (riboflavin), B6 (pyridoxine, pyridoxal, or pyridoxamine, or pyridoxine hydrochloride), vitamin B9 (folic acid or folate), and vitamin B12 (cyanocobalamin).
  • the composition may comprise further B vitamins, further B vitamins as used herein are vitamin B1 , B3, B5 and B7 which the composition may comprise in addition to the one or more of vitamin B2, vitamin B6 and vitamin B9.
  • the vitamin B1 is preferably present in an amount to provide a daily dosage in the range of 0.7 to 5 mg, preferably in the range of 0.8 to 4.9 mg, more preferably in the range of 0.9 to 4.8 mg.
  • the daily amount of vitamin B1 administered is preferably 1 .2 to 5.5 mg per day, more preferably 1 .5 to 5 mg per day, most preferably 1 .6 to 4.8 mg per day.
  • the daily amount of vitamin B1 administered is preferably 0.7 to 2.9 mg per day, more preferably 0.8 to 2.8 mg per day, most preferably 0.9 to 2.7 mg per day.
  • the composition preferably comprises 0.1 to 0.9 mg vitamin B1 per 100 ml, more preferably 0.15 to 0.8 mg vitamin B1 per 100 ml, more preferably 0.2 to 0.75 mg vitamin B1 per 100 ml.
  • the nutrional compostion according to the invention may comprise 0.05 to 0.4 mg vitamin B1 per 100 kcal, preferably 0.1 to 0.35 mg vitamin B1 per 100 kcal, more preferably 0.15 to 0.30 vitamin B1 per 100 kcal based on the total energy content of the composition.
  • the above numbers are based on the molar weight of thiamin.
  • Vitamin B2 or riboflavin is a starting compound in the synthesis of the co-enzymes flavin mononucleotide (FMN, also known as riboflavin-5'-phosphate) and flavin adenine dinucleotide (FAD).
  • FMN flavin mononucleotide
  • FAD flavin adenine dinucleotide
  • the latter coenzymes are critically involved in energy metabolism, cellular respiration, growth and development as well as co-factors in the metabolism of essential fatty acids in brain lipids.
  • a high proportion (>50%) of acute ischemic stroke patients has been reported to be riboflavin deficient as indicated by high red blood cell glutathione reductase activation coefficient (EGRAC) (Gariballa, S. et al. Eur J Clin Nutr, 2007).
  • EGRAC red blood cell glutathione reductase activation coefficient
  • the vitamin B2 is preferably present in an amount to provide a daily dosage in the range of 0.8 to 7.6 mg, preferably in the range of 1 to 7.4 mg, more preferably in the range of 1 .2 to 7.2 mg per day.
  • the daily amount of vitamin B2 administered is preferably 2 to 7.6 mg per day, more preferably 2.2 to 7.4 mg per day, most preferably
  • the daily amount of vitamin B2 administered is preferably 0.8 to 4 mg per day, more preferably 1 to 3.8 mg per day, most preferably 1.2 to 3.6 mg per day.
  • thecomposition preferably comprises 0.1 - 1.4 mg vitamin B2 per 100 ml, more preferably 0.2 - 1 .2 mg vitamin B2 per 100 ml, more preferably 0.3 - 1 mg vitamin B2 per 100 ml.
  • the nutrional compostion according to the invention may comprise 0.4 to 0.6 mg vitamin B2 per 100 kcal, preferably 0.15 to 0.5 mg vitamin B2 per 100 kcal, more preferably 0.2 to 0.4 mg vitamin B2 per 100 kcal based on the total energy content of the composition.
  • the above numbers are based on the molar weight of riboflavin.
  • the vitamin B3 is preferably present in an amount to provide a daily dosage in the range of 3 to 45 mg, preferably in the range of 3.5 to 42 mg, more preferably in the range of 3.8 to 40 mg niacin equivalent per day.
  • the daily amount of vitamin B3 administered is preferably 11 to 42 mg per day, more preferably 12 to 40 mg per day, most preferably 12.5 to 39 mg niacin equivalents per day.
  • the daily amount of vitamin B3 administered is preferably 3.4 to 20 mg per day, more preferably 3.6 to 19 mg per day, most preferably 3.8 to 18 mg niacin equivalents per day.
  • thecomposition preferably comprises 1.2 to 6 mg niacin equivalent per 100 ml, more preferably 1.4 to
  • the nutrional compostion according to the invention may comprise 1 to 2.5 mg niacin equivalent per 100 kcal, preferably 1.1 to 2.2 mg niacin equivalent per 100 kcal, more preferably 1.2 to 2 mg niacin equivalent per 100 kcal based on the total energy content of the composition.
  • the above numbers are based on the molar weight of niacin.
  • the vitamin B5 is preferably present in an amount to provide a daily dosage in the range of 0.8 to 15 mg, preferably in the range of 1 to 14 mg, more preferably in the range of 1 .2 to 13 mg per day.
  • the daily amount of vitamin B5 administered is preferably 3.5 to 14 mg per day, more preferably 4 to 13 mg per day, most preferably 4.1 to 12.6 mg per day.
  • the daily amount of vitamin B5 administered is preferably 0.8 to 7.5 mg per day, more preferably 1 to 7 mg per day, most preferably 1 .2 to 6.8 per day.
  • thecomposition preferably comprises 0.3 to 2.2 mg vitamin B5 per 100 ml, more preferably 0.4 to 2 mg vitamin B5 per 100 ml, more preferably 0.5 to 1.8 mg vitamin B5 per 100 ml.
  • the nutrional compostion according to the invention may comprise 0.2 to 1 mg vitamin B5 per 100 kcal, preferably 0.3 to 0.9 mg vitamin B5 per 100 kcal, more preferably 0.4 to 0.8 mg vitamin B5 per 100 kcal based on the total energy content of the composition.
  • the above numbers are based on the molar weight of panthotenic acid.
  • vitamin B6 pyridoxal 5'-phosphate (PLP)
  • PGP pyridoxal 5'-phosphate
  • the vitamin B6 is preferably present in an amount to provide a daily dosage in the range of 0.7 to 9 mg, preferably in the range of 0.8 to 8 mg, more preferably in the range of 0.9 to 7.5 mg.
  • the daily amount of vitamin B6 administered is preferably 1 .5 to 9 mg per day, more preferably 2 to 8 mg per day, most preferably 2.5 to 7.5 mg per day.
  • the daily amount of vitamin B6 administered is preferably 0.7 to 3.5 mg per day, more preferably 0.8 to 3 mg per day, most preferably 0.9 to 2.7 mg per day.
  • thecomposition preferably comprises 0.2 to 1 mg vitamin B6 per 100 ml, more preferably 0.25 - 0.8 mg vitamin B6 per 100 ml, more preferably 0.3 to 0.7 mg vitamin B6 per 100 ml.
  • the compostion according to the invention may comprise 0.1 to 0.5 mg vitamin B6 per 100 kcal, preferably 0.2 to 0.4 mg vitamin B6 per 100 kcal, more preferably 0.25 to 0.3 mg vitamin B6 per 100 kcal based on the total energy content of the composition.
  • the above numbers are based on the molar weight of pyridoxine.
  • the vitamin B7 is preferably present in an amount to provide a daily dosage in the range of 8 to 95 pg, preferably in the range of 9 to 90 pg, more preferably in the range of 9.5 to 85 pg per day.
  • the daily amount of vitamin B7 administered is preferably 24 to 95 pg per day, more preferably 26 to 90 pg per day, most preferably 28 to 88 pg per day.
  • the daily amount of vitamin B7 administered is preferably 9.4 to 45 pg per day, more preferably 9.6 to 42 pg per day, most preferably 9.8 to 41 pg per day.
  • thecomposition preferably comprises 2 to 14 pg vitamin B7 per 100 ml, more preferably 3 to 12 pg vitamin B7 per 100 ml, more preferably 3.5 to 11 pg vitamin B7 per 100 ml.
  • the compostion according to the invention may comprise 1 .5 to 6 pg vitamin B7 per 100 kcal, preferably 2 to 5.5 pg vitamin B7 per 100 kcal, more preferably 2.5 to 5 pg vitamin B7 per 100 kcal based on the total energy content of the composition.
  • the above numbers are based on the molar weight of biotin.
  • Vitamin B9 or folic acid is an essential nutrient that id converted by the body into folate, which is required for DNA and RNA biosynthesis, DNA repair and one-carbon metabolic reactions. Decreased folate levels have frequently been reported in stroke patients and have been associated with hyperhomocysteinemia which is common in stroke patients (Poddar, R, Exp Neurol, 2021).
  • the vitamin B9 is preferably present in an amount to provide a daily dosage in the range of 150 to 900 pg, preferably in the range of 175 to 800 pg, more preferably in the range of 200 to 750 pg per day.
  • the daily amount of vitamin B9 administered is preferably 200 to 800 pg per day, more preferably 225 to 775 pg per day, most preferably 240 to 750 pg per day.
  • the daily amount of vitamin B9 administered is preferably 150 to 700 pg per day, more preferably 175 to 650 pg per day, most preferably 200 to 600 pg per day.
  • thecomposition preferably comprises 20 to 225 pg vitamin B9 per 100 ml, more preferably 25 to 200 pg vitamin B9 per 100 ml, more preferably 30 to 175 pg vitamin B9 per 100 ml.
  • the compostion according to the invention may comprise 16 to 80 pg vitamin B9 per 100 kcal, preferably 18 to 75 pg vitamin B9 per 100 kcal, more preferably 20 to 70 pg vitamin B9 per 100 kcal based on the total energy content of the composition. The above numbers are based on the molar weight of folic acid.
  • the vitamin B12 is preferably present in an amount to provide a daily dosage in the range of 2 to 20 pg, preferably in the range of 2.5 to 19 pg, more preferably in the range of 3 to 18 pg per day.
  • the daily amount of vitamin B9 administered is preferably 4 to 22 pg per day, more preferably 5 to 20 pg per day, most preferably 6 to 18 pg per day.
  • the daily amount of vitamin B9 administered is preferably 2 to 12 pg per day, more preferably 2.5 to 10 pg per day, most preferably 3 to 9 pg per day.
  • thecomposition preferably comprises 0.5 to 3 pg vitamin B12 per 100 ml, more preferably 0.6 to 2.6 pg vitamin B12 per 100 ml, more preferably 0.7 to 2.4 pg vitamin B12 per 100 ml.
  • the compostion according to the invention may comprise 0.4 to 1 .4 pg vitamin B12 per 100 kcal, preferably 0.5 to 1 .2 pg vitamin B12 per 100 kcal, more preferably 0.6 to 1 pg vitamin B12 per 100 kcal based on the total energy content of the composition.
  • the above numbers are based on the molar weight of cyanocobalamin. n-3 PUFA
  • the present composition optionally further comprises omega-3 polyunsaturated fatty acids (PUFA), preferably n-3 LC-PUFA (long-chain PUFAs).
  • PUFA omega-3 polyunsaturated fatty acids
  • the composition comprises at least one, preferably two omega-3 long-chain polyunsaturated fatty acids (LC-PUFA; having a chain length of 18 and more carbon atoms) selected from the group consisting of docosahexaenoic acid (22:6, co-3; DHA), eicosapentaenoic acid (20:5, co-3; EPA) and docosapentaenoic acid (22:5 co-3; DPA), preferably DHA and EPA.
  • LC-PUFA omega-3 long-chain polyunsaturated fatty acids
  • EPA is converted to DPA (OJ-3), increasing subsequent conversion of DPA to DHA in the brain.
  • the present composition preferably contains a significant amount of EPA, so to further stimulate in vivo DHA formation.
  • the DHA, EPA and/or DPA may be provided in any form such as, but not limited to, triglycerides, diglycerides, monoglycerides, free fatty acids or their salts or esters, phospholipids, lysophospholipids, glycerol ethers, lipoproteins, ceramides, glycolipids or combinations thereof.
  • the present composition comprises at least DHA in triglyceride form.
  • Suitable OJ-3 LCPUFA and/or sources of DHA and EPA include tuna oil, (other) fish oils, DHA-rich alkyl esters, algae oil, egg yolk, krill oil or phospholipids enriched with OJ-3 LCPUFA e.g. phosphatidylserine- DHA.
  • the composition or composition for use according to the invention comprises fish oil providing the omega-3 LCPUFA(s).
  • Another particularly suitable source for the omega-3 LCPUFA(s) is algae oil.
  • DHA is preferably administered in an amount of 100 to 1250 mg per day, more preferably 150 to 1200 mg per day, even more preferably 200 to 1100 mg per day, most preferably 250 to 1000 mg per day.
  • the daily amount of DHA administered is preferably 200 to 1100 mg per day, more preferably 250 to 1050 mg per day, most preferably 300 to 1000 mg per day.
  • the daily amount of DHA administered is preferably 150 to 850 mg per day, more preferably 200 to 800 mg per day, most preferably 250 to 750 mg per day.
  • the present composition preferably comprises 30 to 240 mg DHA per 100 ml of the composition, preferably 35 to 220 mg DHA per 100 ml, more preferably 40 to 200 mg DHA per 100 ml composition.
  • the nutrional compostion according to the invention comprises 20 to 100 mg DHA per 100 kcal, preferably 25 to 90 mg DHA per 100 kcal, more preferably 30 to 80 mg DHA per 100 kcal based on the total energy content of the nutritional composition.
  • the above numbers are based on the molar weight of DHA.
  • EPA is preferably administered in an amount of 300 to 2400 mg per day, more preferably 400 to 2200 mg per day, most preferably 500 to 2000 mg per day.
  • the daily amount of EPA administered is preferably 500 to 2300 mg per day, more preferably 600 to 2100 mg per day, most preferably 650 to 2000 mg per day.
  • the daily amount of EPA administered is preferably 300 to 1750 mg per day, more preferably 400 to 1600 mg per day, most preferably 500 to 1500 mg per day.
  • the present composition preferably comprises 70 to 440 mg EPA per 100 ml of the composition, preferably 80 to 420 mg EPA per 100 ml, more preferably 90 to 400 mg EPA per 100 ml composition.
  • the nutrional compostion according to the invention comprises 50 to 225 mg EPA per 100 kcal, preferably 60 to 200 mg EPA per 100 kcal, more preferably 70 to 170 mg EPA per 100 kcal based on the total energy content of the nutritional composition.
  • the above numbers are based on the molar weight of EPA.
  • the weight ratio of DHA to EPA is preferably lower than 1 , more preferably 1 :1.1 to: 1 :4, more preferably 1 :1 .3 to 1 :2.5. In some embodiments de weight ratio of DHA to EPA is about 1 :2.
  • the present use and method preferably comprises the administration of 400 to 3750 mg n-3 LC-PUFAs (preferably DHA+EPA+DPA, most preferably DHA+EPA) per day, more preferably 550 to 3500 mg per day, even more preferably 650 to 3250 mg per day, most preferably 750 to 3000 mg per day.
  • n-3 LC-PUFAs preferably DHA+EPA+DPA, most preferably DHA+EPA
  • the present composition preferably comprises of n-3 LC-PUFA (more preferably DHA+EPA+DPA, most preferably DHA+EPA) on the total fatty acids is preferably 1 to 8 wt%, more preferably 1 .5 to 7.5 wt%, most preferably 2 to 7 wt%.
  • the present composition preferably comprises 0.1 to 3.5 wt% DHA based on total fatty acids, preferably 0.3 to 3 wt% DHA based on total fatty acids, more preferably 0.5 to 2.5 wt% DHA based on total fatty acids.
  • the present composition preferably comprises 0.5 to 6 wt% EPA based on total fatty acids, preferably 1 to 5 wt% EPA, most preferably 1 .5 to 4.5 wt%, based on total fatty acids.
  • the present composition preferably optionally further comprises choline.
  • Choline may be present as such, or as choline equivalent in the form of a choline salt and/or choline ester.
  • the choline salt is preferably selected from choline chloride, choline bitartrate, or choline stearate.
  • the choline ester is preferably selected from a phosphatidylcholine and lyso-phosphatidyl choline, preferably phosphatidylcholine.
  • the present composition comprises a) choline as such or a choline salt and b) a choline ester, preferably phosphatidylcholine.
  • the present composition preferably comprises both choline as such or a choline salt and in addition a choline ester, preferably phosphatidylcholine.
  • the present composition for use and method preferably comprises the administration of more than 70 mg of a) choline or choline salt per day, preferably 70 to 1300 mg per day, more preferably 80 to 1200 mg per day, most preferably 100 to 1100 mg per day.
  • the daily amount of choline or choline salt administered is preferably 200 to 1400 mg per day, more preferably 300 to 1200 mg per day, most preferably 350 to 1100 mg per day.
  • the daily amount of choline or choline salt administered is preferably 70 to 500 mg per day, more preferably 80 to 400 mg per day, most preferably 100 to 300 mg per day.
  • the present composition preferably comprises 30 to 180 mg a) choline or choline salts per 100 ml of the liquid composition, preferably 35 mg to 170 mg choline per 100 ml, more preferably 40 to 160 mg choline per 100 ml composition, most preferably 45 mg to 150 mg choline per 100 ml.
  • the nutrional compostion according to the invention comprises 25 to 110 mg choline per 100 kcal, preferably 30 to 105 mg choline per 100 kcal, more preferably 33 to 100 mg per 100 kcal based on the total energy content of the nutritional composition.
  • the above numbers are based on choline, the amounts of choline salts or esters can be calculated taking the molar equivalent to choline into account.
  • the present composition may comprise choline in the form of a choline ester, preferably provided in the form of phospholipids.
  • one or more phospholipid(s) is/are present in the composition according to the invention.
  • the one or more phospholipid(s) is/are selected from the group consisting of phosphatidic acid (PA), phosphatidylethanolamine (PE), phosphatidylcholine (PC), phosphatidylserine (PS) and phosphoinositides (PI), preferably at least phosphatidyl choline.
  • Phospholipids are in a preferred embodiment a source of the choline ester phosphatidylcholine.
  • Suitable sources of phospholipids herein are soya lecithin, egg lecithin as well as rapeseed and sunflower lecithin.
  • Milk contains phospholipids in the milk fat globule membrane (MFGM), suitable sources include milk phospholipid concentrate such as those commercially available from Lecico GmbH, whey protein concentrate Lacprodan®
  • phospholipids comprise about 10 to 40 wt% of phosphatidylcholine.
  • the composition and use or method of use of the composition preferably comprises the administration of phospholipids in an amount of 0.6 to 6.6 g mg per day, preferably 0.8 to 6.4 g of phospholipids per day, more preferably 0.9 to 6.2 g of phospholipids per day, most preferably 1 to 6 g of phospholipids per day.
  • the amount of phospholipids is about 200 mg per day.
  • the phospholipids preferably at least provide phosphatidylcholine.
  • the present composition preferably comprises phospholipids in an amount of 150 and 900 mg per 100 ml, more preferably between 200 and 850 mg per 100 ml, most preferably 250 to 800 mg per 100 ml.
  • the phospholipids preferably at least provide phosphatidylcholine.
  • the daily amount of phospholipids administered is preferably 1 to 7 g per day, more preferably 1 .5 to 6.5 g per day, most preferably 2 to 6 g per day.
  • the daily amount of phospholipids administered is preferably 0.5 to 4 g per day, more preferably 0.75 to 3.5 g per day, most preferably 1 to 3 g per day.
  • the nutrional compostion according to the invention comprises 100 to 500 mg of phospholipids per 100 kcal, preferably 150 to 400 mg of phospholipids per 100 kcal, more preferably 200 to 350 mg of phospholipids per 100 kcal based on the total energy content of the nutritional composition.
  • the nutritional composition according to the invention comprises a) choline or choline salts and b) phosphatidylcholine (PC).
  • the weight to weight ratio phosphatidylcholine to choline is usually more than 0.1 , preferably more than 0.26, in particular 0.30-6, more preferably 0.36-3.
  • the ratio phosphatidylcholine to choline is in the range of 40:60 to 60:40.
  • the amount of choline in grams is to be calculated as the molar contribution of choline as provided by all choline sources (when orally digested and assuming 100% bioavailability, including PC), times the molecular weight of choline (104 g/mol).
  • choline (salt) content can be reduced, whilst still providing a bioavailable choline source.
  • dietary choline can be metabolized in the gut into trimethylamine (TMA) which in turn is oxidized in the liver into trimethylamine N-oxide (TMAO).
  • TMA trimethylamine
  • TMAO trimethylamine N-oxide
  • Both TMA and TMAO have been associated with an increased risk of cardiovascular diseases (Zhu et al, Cell 2016; Jaworska et al. Cardiovac. Res 2019) and therefore it is preferred to provide choline both in free (salt) form and as phosphatidylcholine.
  • composition according to the invention comprising the combination of (i) co-enzyme Q10 with (ii) vitamin D and (iii) vitamin B2 optionally in combination with one or more of vitamin B6, and B9, and optionally (iv) polyunsaturated fatty acids and/or (v) choline further comprises one of more selected from A, further B, C, and E vitamin(s), phospholipids, selenium and magnesium. More preferred the composition contains two or more of these further ingredients. The further ingredients and their respective amounts will be discussed hereinafter.
  • the present composition may further comprise vitamin A.
  • Vitamin A is a fat-soluble vitamin which comes in several forms (as retinol, retinal, retinoic acid or retinyl ester). Any functional form of vitamin A known in the art is suitable to be used herein, including retinol (in particular retinol esters), retinal, retinoic acid, beta-carotene, provitamin A, or any combination thereof.
  • the composition comprises retinol, in particular retinyl acetate and/or retinyl palmitate.
  • Vitamin A intakes or requirements are generally expressed in terms of retinol equivalents (RE).
  • RE retinol equivalents
  • One RE is defined as the biological activity associated with 1 pg of all-trans retinol.
  • 1 pg Retinol Equivalent is similar to 1 pg of all-trans retinol.
  • 1 International Unit (IU) retinol corresponds to 0.3 pg Retinol Equivalents.
  • vitamin A is preferably administered in an amount of 300 to 2800 pg Retinol Equivalents per day, more preferably 350 to 2700 pg Retinol Equivalents per day, even more preferably 650 to 900 pg Retinol Equivalents per day, most preferably 375 to 2600 pg Retinol Equivalents per day.
  • the composition is in the form of a tube feed and the daily amount of vitamin A administered is preferably 700 to 2850 pg Retinol Equivalents per day, more preferably 800 to 2750 pg Retinol Equivalents per day, most preferably 850 to 2600 pg Retinol Equivalents per day.
  • composition in the form of a oral nutritional supplement and the daily amount of vitamin A administered is preferably 300 to 1200 pg Retinol Equivalents per day, more preferably 350 to 1150 pg Retinol Equivalents per day, most preferably 375 to 1125 pg Retinol Equivalents per day.
  • the present composition may preferably comprise vitamin A, preferably 50 to 400 pg Retinol Equivalents per 100 ml of the composition, more preferably 75 to 350 pg Retinol Equivalents per 100 ml, most preferably 100 to 300 pg Retinol Equivalents per 100 ml composition.
  • the nutrional compostion according to the invention may comprise 60 to 150 pg Retinol Equivalents per 100 kcal, preferably 70 to 140 pg Retinol Equivalents per 100 kcal, more preferably 80 to 130 pg Retinol Equivalents per 100 kcal based on the total energy content of the nutritional composition.
  • the present composition may further comprise vitamin C.
  • Vitamin C is an antioxidant that may provide beneficial characteristics during and after a period of hypoxia such as a stroke.
  • Vitamin C includes functional equivalents thereof including sodium ascorbate and calcium ascorbate, and may be present in an amount to provide a daily dosage in the range of 75 to 700 mg, preferably in the range of 85 to 600 mg, more preferably in the range of 95 to 550 mg per day.
  • the daily amount of vitamin C administered is preferably 140 to 600 mg per day, more preferably 160 to 575 mg per day, most preferably 180 to 550 mg per day.
  • the daily amount of vitamin C administered is preferably 80 to 320 mg per day, more preferably 90 to 300 mg per day, most preferably 95 to 290 mg per day.
  • vitamin C is present in an amount in the range of 10 to 100 mg, preferably in the range of 15 to 90 mg, more preferably in the range of 20 to 80 mg per 100 ml of the composition.
  • the compostion according to the invention may comprise 12 to 40 mg vitamin C per 100 kcal, preferably 14 to 35 mg vitamin C per 100 kcal, more preferably 16 to 32 mg vitamin C per 100 kcal based on the total energy content of the composition.
  • the above numbers are based on the molar weight of ascorbic acid.
  • composition according to the invention may comprise vitamin E.
  • Vitamin E refers to compounds having vitamin E activity as known in the art, typically tocopherol and/or an equivalent thereof.
  • vitamin E may be present in the composition in an amount to provide a daily dosage in the range of 8 to 75 mg, preferably in the range of 10 to 70 mg, more preferably in the range of 12.5 to 70 mg alpha-TE.
  • the daily amount of vitamin E administered is preferably 18 to 80 mg per day, more preferably 20 to 75 mg per day, most preferably 22 to 70 mg alpha-TE per day.
  • the daily amount of vitamin E administered is preferably 8 to 42 mg per day, more preferably 10 to 40 mg per day, most preferably 12.5 to 37.5 mg alpha-TE per day.
  • Such amounts of vitamin E prevent oxidative damage to the injury site.
  • tocopherol and/or equivalent is present in an amount in the range of 2 to 14 mg alpha-TE, preferably in the range of 2.5 to 12 mg alpha-TE, more preferably in the range of 2.75 to 10 mg alpha-TE per 100 ml of the composition.
  • the compostion according to the invention may comprise 1 to 5.5 mg alpha-TE per 100 kcal, preferably 1.5 to 5 mg alpha-TE per 100 kcal, more preferably 2 to 4.5 mg alpha-TE per 100 kcal based on the total energy content of the composition.
  • tocopherol and/or an equivalent thereof comprises tocopherols (e.g. alpha- and gamma-), tocotrienols, pharmaceutical and/or nutritional acceptable derivatives thereof and any combination thereof.
  • tocopherols e.g. alpha- and gamma-
  • tocotrienols e.g. tocotrienols
  • pharmaceutical and/or nutritional acceptable derivatives thereof e.g. pharmaceutical and/or nutritional acceptable derivatives thereof and any combination thereof.
  • alpha-tocopherol equivalents alpha- TE
  • composition according to the invention may optionally comprise vitamin K, preferably vitamin K1 , although it is preferred that the composition does not comprise or comprise minimal amounts of vitamin K.
  • Vitamin K is a general name for a group of compounds containing a 2-methyl-1 ,4-naphthoquinone nucleus with different lipophilic side chains at position 3, in the following also referred to as “the K- vitamins”. Vitamin K naturally occurs in the form of vitamin K1 (phytomenadione, phytonadione, a- phylloquinone) and vitamin K2 (menaquinone) which is produced by gastrointestinal bacteria in basically two different sub-types, namely vitamin K2(35) (C46H64O2) and vitamin K2(30) (C41 H56O2). Vitamin K3 (menadione) is a pro-vitamin which can be converted to vitamin K2 by animals.
  • the vitamin K1 is preferably present in a daily dosage at most 240 pg, preferably at most 200 pg, more preferably at most 100 pg per day.
  • the present composition preferably comprises less than 40 pg vitamin K1 per 100 ml, more preferably less than 35 pg vitamin K1 per 100 ml, more preferably less than 30 pg vitamin K1 per 100 ml.
  • the compostion according to the invention may comprise less than 18 pg vitamin K1 per 100 kcal, preferably less than 16 pg vitamin K1 per 100 kcal, more preferably less than 15 pg vitamin K1 per 100 kcal based on the total energy content of the composition.
  • the above numbers are based on the molar weight of phylloquinone.
  • the composition comprises less than 15 pg vitamin K1 per 100 kcal.
  • the present composition may comprise selenium.
  • the antioxidant activity of selenium may advantageously prevent and/or inhibit damages to brain areas.
  • selenium is preferably present in an amount to provide a daily dosage in the range of 30 to 275 pg, preferably in the range of 35 to 250 pg, more preferably in the range of 38 to 225 pg per day.
  • the daily amount of selenium administered is preferably 60 to 275 pg per day, more preferably 70 to 250 pg per day, most preferably 75 to 225 pg per day.
  • the daily amount of selenium administered is preferably 25 to 140 pg per day, more preferably 30 to 130 pg per day, most preferably 35 to 120 pg per day.
  • the present composition preferably comprises 8 to 45 pg selenium per 100 ml, more preferably 10 to 40 pg selenium per 100 ml, more preferably 11 to 35 pg selenium per 100 ml.
  • the compostion according to the invention may comprise 4 to 18 pg selenium per 100 kcal, preferably 6 to 16 pg selenium per 100 kcal, more preferably 8 to 14 pg selenium per 100 kcal based on the total energy content of the composition.
  • the present composition may comprise magnesium.
  • Magnesium plays an essential role in nerve transmission and neuromuscular conduction. It also functions in a protective role against excessive excitation that can lead to neuronal cell death (excitotoxicity).
  • magnesium is preferably present in an amount to provide a daily dosage in the range of 125 to 850 mg, preferably in the range of 150 to 800 mg, more preferably in the range of 170 to 750 mg per day.
  • the daily amount of magnesium administered is preferably 200 to 780 mg per day, more preferably 220 to 760 mg per day, most preferably 240 to 740 mg per day.
  • the daily amount of magnesium administered is preferably 150 to 600 mg per day, more preferably 160 to 550 mg per day, most preferably 170 to 525 mg per day.
  • the present composition preferably comprises 20 to 160 mg magnesium per 100 ml, more preferably 25 to 150 mg magnesium per 100 ml, more preferably 30 to 140 mg magnesium per 100 ml. Based on calories, preferably the compostion according to the invention may comprise 10 to 70 mg magnesium per 100 kcal, preferably 15 to 65 magnesium per 100 kcal, more preferably 20 to 60 mg magnesium per 100 kcal based on the total energy content of the composition.
  • composition may comprise further minerals including but not limited to sodium, potassium, chloride, calcium, phosphor, iron, zinc, cupper, manganese, fluor, molybdenum, chrome and iodium. Amount thereof comply with general recommendations for nutritional requirements of the FSMP. 1
  • the lipid fraction may in addition to the LC-PUFAs further comprise lipids that are a source of essential fatty acids alpha-linolenic acid (ALA, C-18:3) and linoleic acid (LA, C-18:2).
  • LA and/or ALA may be provided as free fatty acids, in triglyceride form, in diglyceride form, in monoglyceride form, in phospholipid form, or as a mixture of one of more of the above.
  • the present composition contains at least one, preferably at least two lipid sources selected from the group consisting of soybean oil, rape seed oil (such as colza oil, low erucic acid rape seed oil and canola oil), high oleic sunflower oil, high oleic safflower oil and olive oil.
  • the LA:ALA weight ratio is preferably in the range of 8:1 to 3:1 , preferably 7:1 to 4:1 , more preferably 6:1 to 5:1.
  • the present composition preferably comprises 0.2 to 3.5 g LA per 100 ml, more preferably 0.3 to 3 g LA per 100 ml, more preferably 0.4 to 2.5 g LA per 100 ml.
  • the compostion according to the invention may comprise 0.1 to 1.5 g LA per 100 kcal, preferably 0.2 to 1.1 g LA per 100 kcal, more preferably 0.25 to 1 g LA per 100 kcal based on the total energy content of the composition.
  • the present composition preferably comprises 0.02 to 0.2 g ALA per 100 ml, more preferably 0.05 to 0.15 g ALA per 100 ml, more preferably 0.06 to 0.1 g ALA per 100 ml.
  • the compostion according to the invention may comprise 0.03 to 0.08 g ALA per 100 kcal, preferably 0.04 to 0.07 g ALA per 100 kcal, more preferably 0.05 to 0.065 g ALA per 100 kcal based on the total energy content of the composition.
  • composition suitable for subjects that suffered from a stroke, preferably an ischemic stroke.
  • Such a nutritional composition according to the invention suitably comprises a combination of (i) coenzyme Q10 with (ii) vitamin D and (iii) vitamin B2, optionally further comprising (iv) polyunsaturated fatty acids and/or (v) choline.
  • the composition comprises a combination of co-enzyme Q10 vitamin D and vitamin B2, in combination with one or more of B6, and B9.
  • the composition according to the invention further comprises one of more selected from A, further B, C and E vitamin(s), phospholipids, selenium and magnesium.
  • the composition according to the invention further comprises one of more selected from A, B, C and E vitamin(s), phospholipids, selenium and magnesium.
  • the composition according to the invention further comprises one or more of vitamin B1 , B6, B9 and vitamin B12.
  • the composition comprises vitamin D3, co-enzyme Q10, vitamin B2, polyunsaturated fatty acids, choline and one or more, preferably all, of vitamin B1 , B6, B9, B12, vitamin A, vitamin C, vitamin E, selenium, magnesium and phospholipids.
  • composition according to the invention comprises per daily dosage
  • composition according to the invention comprises per daily dosage
  • choline 200 to 1400 mg, preferably 300 to 1200 mg, more preferably 350 to 1100 mg choline based on molar weight of choline, wherein choline is selected from free choline, choline salts and/or choline esters, preferably at least phosphatidylcholine.
  • composition according to the invention comprises per daily dosage
  • choline 200 to 1400 mg, preferably 300 to 1200 mg, more preferably 350 to 1100 mg choline, wherein choline is selected from free choline, choline salts and/or choline esters, preferably at least phosphatidylcholine.
  • 300 to 2400 mg preferably 400 to 2200 mg, more preferably 500 to 2000 mg per day EPA; (v) 200 to 1400 mg, preferably 300 to 1200 mg, more preferably 350 to 1100 mg choline, wherein choline is selected from free choline, choline salts and/or choline esters, preferably at least phosphatidylcholine.
  • choline 200 to 1400 mg, preferably 300 to 1200 mg, more preferably 350 to 1100 mg choline, wherein choline is selected from free choline, choline salts and/or choline esters, wherein the composition preferably comprises v a ) phosphatidylcholine and Vb) choline or a salt thereof, and wherein the weight to weight ratio of phosphatidylcholine to choline is more than 0.1 .
  • choline 200 to 1400 mg, preferably 300 to 1200 mg, more preferably 350 to 1100 mg choline, wherein choline is selected from free choline, choline salts and/or choline esters, preferably at least phosphatidylcholine.
  • choline 200 to 1400 mg, preferably 300 to 1200 mg, more preferably 350 to 1100 mg choline, wherein choline is selected from free choline, choline salts and/or choline esters, wherein the composition preferably comprises v a ) phosphatidylcholine and Vb) choline or a salt thereof, and wherein the weight to weight ratio of phosphatidylcholine to choline is more than 0.1 .
  • composition comprising per daily dosage a combination of (i) (ii) and (iii), at least one of (vi) and (vii) and optionally (iv) and/or (v) further comprises one or more of
  • composition comprising per daily dosage a combination of (i) (ii), (iii) ,(iv) and (v) at least one of (vi) and (vii) and one or more of
  • composition comprises per daily dosage a combination of (i) (ii) and (iii), at least one of (vi) and (vii) and optionally (iv) and/or (v), one or more selected of (vii) - (xiv) further comprises at least one of
  • liquid nutritional composition comprising per 100 ml
  • liquid nutritional composition comprising per 100 ml
  • choline 35 to 170 mg, preferably 40 to 160 mg, more preferably 45 to 150 mg choline, wherein choline is selected from free choline, choline salts and/or choline esters, preferably at least phosphatidylcholine.
  • liquid nutritional composition comprising per 100 ml
  • liquid nutritional composition comprising per 100 ml
  • choline 35 to 170 mg, preferably 40 to 160 mg, more preferably 45 to 150 mg choline, wherein choline is selected from free choline, choline salts and/or choline esters, preferably at least phosphatidylcholine.
  • liquid nutritional composition comprising per 100 ml
  • choline 35 to 170 mg, preferably 40 to 160 mg, more preferably 45 to 150 mg choline, wherein said choline is selected from free choline, choline salts and/or choline esters, preferably at least phosphatidylcholine and, wherein the composition preferably comprises v a ) phosphatidylcholine and Vb) choline or a salt thereof, and wherein the weight to weight ratio of phosphatidylcholine to choline is more than 0.1 .
  • a liquid nutritional composition comprising per 100 ml, (i) 1 to 15 mg, preferably 1 .5 to 14 mg, more preferably 2 to 13 mg co-enzyme Q10; with
  • a liquid nutritional composition comprising per 100 ml: i) 1 to 15 mg, preferably 1 .5 to 14 mg, more preferably 2 to 13 mg co-enzyme Q10; with
  • a liquid nutritional composition comprising per 100 ml: i) 1 to 15 mg, preferably 1 .5 to 14 mg, more preferably 2 to 13 mg co-enzyme Q10;
  • a liquid nutritional composition comprising per 100 ml: i) 1 to 15 mg, preferably 1 .5 to 14 mg, more preferably 2 to 13 mg co-enzyme Q10;
  • choline 35 to 170 mg, preferably 40 to 160 mg, more preferably 45 to 150 mg choline, wherein said choline is selected from free choline, choline salts and/or choline esters, preferably at least phosphatidylcholine and, wherein the composition preferably comprises v a ) phosphatidylcholine and Vb) choline or a salt thereof, and wherein the weight to weight ratio of phosphatidylcholine to choline is more than 0.1 ; and at least one of (vi) and (vii);
  • liquid nutritional composition comprising per 100 ml a combination of (i) and (ii), (iii), at least one of (vi) and (vii) and optionally (iv) and/or to (v), further comprises one or more of
  • liquid nutritional composition may further comprise per 100 ml one of more of
  • liquid nutritional composition comprising per 100 kcal
  • liquid nutritional composition comprising per 100 kcal
  • a liquid nutritional composition comprising per 100 kcal
  • liquid nutritional composition comprising per 100 kcal
  • choline 100 to 1000 mg, preferably 200 to 800 mg, more preferably 300 to 500 mg choline, wherein said choline is selected from free choline, choline salts and/or choline esters, preferably at least phosphatidylcholine and, wherein the composition preferably comprises v a ) phosphatidylcholine and Vb) choline or a salt thereof, and wherein the weight to weight ratio of phosphatidylcholine to choline is more than 0.1 .
  • liquid nutritional composition comprises per 100 kcal
  • liquid nutritional composition comprising per 100 kcal:
  • the liquid nutritional composition comprises per 100 kcal a combination of (i) (ii) and (iii), at least one of (vi) and (vii) and optionally (iv) and/or to (v), further comprises one or more of
  • liquid nutritional composition may further comprise per 100 kcal one of more of
  • vitamin D preferably vitamin D3
  • vitamin D preferably vitamin D3
  • choline choline, choline salts and/or choline ester, preferably at least phosphatidyl choline;
  • An exemplary enteral tube feed was formulated comprising per 100 ml 128 kcal and comprising per 100 kcal 4.88 g protein, 4.5 g lipids and 9.3 g carbohydrates.
  • the tube feed comprises ingredients according to table 1 and is for administration to a tube to a patient after an ischemic stroke.
  • An exemplary oral nutritional supplement was formulated comprising per 100 ml 240 kcal and comprising per 100 kcal 6 g protein, 3.89 g lipids and 9.57 g carbohydrates.
  • the nutritional supplement comprises ingredients according to table 2 and is for administration as a drink to patients after an ischemic stroke.
  • Cortical neuronal cultures Mouse primary cortical neurons (E14) were seeded onto 96-well plates coated with poly-D-lysine. Cells (20.000 cells/well) were cultured in modified Neurobasal medium (containing B27, Pen/Strep, and GlutaMAX). Cell cultures were incubated at 37 °C in 5% CO2 and medium was replaced every 2-3 days.
  • Rat primary cortical neurons (E18) were seeded onto 96-well plates coated with poly-D-lysine. Cells (20.000 cells/well) were cultured in Neurobasal medium (containing B27, Pen/Strep, and GlutaMAX). Cell cultures were incubated at 37 °C in 5% CO2 and medium was replaced every 3-4 days.
  • OGD oxygen glucose deprivation
  • modified Neurobasal medium was replaced with neurobasal medium without glucose.
  • hypoxia cells were placed in a Hypoxia Incubator Chamber (Stemcell Technologies) set to 0.1 % 02, 94.9% N2 and 5% CO2 at 37 °C for 3.5 hrs. After the hypoxic incubation period, medium was removed and replaced with modified Neurobasal medium, and plates returned to normoxic conditions and incubated at 37 °C in 5% CO2 for an additional 24 hrs.
  • Nutrient supplementation The effects of nutrient supplementation of neuronal cultures after hypoxia were assessed by comparing different concentrations of vitamin D (150 nM), co-enzyme Q10 (15 pM), vitamin B6 (1.5 pM), or vitamin B9 (2.25 pM) to the vehicle control (0 pM). Nutrients were supplemented either alone, in combination of two, or in combination of three, starting 24h after the OGD and lasting for two days. Every condition was tested in 5-fold. Control cells were exposed to hypoxia but not supplemented with any of vitamin D, B6, B9 or co-enzyme Q10.
  • Example 5 Neurite outgrowth with co-enzyme Q10, vitamin D3, vitamin B2, PUFAs and a source of choline
  • PC12 neurite outgrowth is one of the most widely used cell models for the study of neuronal differentiation.
  • PC12 pheochromocytoma cells were grown in DMEM (Gibco), supplemented with 10% fetal bovine serum (FBS), penicillin (100 units/ml), and streptomycin (100 pg/ml) (Gibco), under a humidified atmosphere with 95% air and 5% CO2 at 37°C.
  • FBS fetal bovine serum
  • penicillin 100 units/ml
  • streptomycin 100 pg/ml
  • Cells were seeded in collagen (0.01 mg/ml) coated 96 well plates at a density of 5000 cells/well and after 24 hours supplemented with medium containing 20 ng/ml nerve growth factor (NGF) with or without coenzyme Q10 (1 pM), vitamin D3 ((0.25 pM), vitamin B2 (0.5 pM), DHA (6.7 pM), a source of choline (20 pM phosphatidylcholine, PC) or a mixture thereof.
  • NGF nerve growth factor
  • DHA Docosahexaenoic acid
  • Supplementation of cells was performed in 6-fold in 96 wells plates. These conditions were compared to non-supplemented cells. After supplementation for 48 hours with these combinations, cells were stained using Calcein-AM stain (2 ng/pl) and the nuclei were counterstained using Hoechst stain (0.6 pg /ml), in 100 pl culture medium per well and incubated for 20 min at 37°C. Subsequently, FITC and DAPI images (9 images per well for 96 wells plate) were taken using an ImageXpress high content imaging system. Neurite length was quantified using the neurite outgrowth module in MetaXpress.
  • Example 6 Neurite outgrowth with choline and/or phosphatidyl choline
  • Nutrients were supplemented alone (100% chol-CI or 100% PC) and in a ratio of 60:40 and 40:60 of chol-CI to PC. Supplementation of cells was performed in 6-fold in 96 wells plates at a total concentration of 20 pM choline, derived from chol-CI, from PC, or from both. The neurite outgrowth in these conditions were compared to non-supplemented PC12 cells.

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  • Inorganic Chemistry (AREA)
  • Hospice & Palliative Care (AREA)
  • Molecular Biology (AREA)
  • Psychiatry (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Coloring Foods And Improving Nutritive Qualities (AREA)

Abstract

L'invention concerne une composition nutritionnelle comprenant une combinaison (i) d'une co-enzyme Q10 avec (ii) de la vitamine D et (iii) de la vitamine B2, destinée à être utilisée dans le traitement d'un accident vasculaire cérébral, de préférence un accident vasculaire cérébral ischémique. L'invention concerne également une composition comprenant une combinaison renfermant une co-enzyme Q10 et de la vitamine D, ainsi que de la vitamine D3 avec éventuellement des acides gras polyinsaturés choisis parmi DHA, EPA et/ou DPA ; et/ou une choline, des sels de choline et/ou des esters de choline.
PCT/EP2023/068080 2022-07-01 2023-06-30 Composition nutritionnelle pour traiter un accident vasculaire cérébral WO2024003377A1 (fr)

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PCT/EP2023/068097 WO2024003385A1 (fr) 2022-07-01 2023-06-30 Composition nutritionnelle pour la neurodégénérescence et le traumatisme neurologique

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